Ontario Cancer Institute Research Articles

Editorial introductions.

Editorial introductions.

Ribophorin II is upregulated in myelodysplastic syndromes and prevents apoptosis and cell cycle progression.

This study explored the role of ribophorin II (RPN2) in myelodysplastic syndromes (MDSs) cell proliferation and growth and revealed that RPN2 knockdown suppressed OCI-AML3 cell growth and proliferation and triggered cell cycle arrest and elicited apoptosis in OCI-AML3 cells. In addition, it shed light on the etiology of RPN2's role in MDS cell proliferation that RPN2 can negatively impact enhancer of zeste homolog-2 (EZH2) expression, which in turn is able to modulate the cell cycle location and death in OCI-AML3 cells. Hence, RPN2 expression could be a latent predictor of prognosis in patients with MDS.

2α-Hydroxyeudesma-4,11(13)-Dien-8β,12-Olide Isolated from Inula britannica Induces Apoptosis in Diffuse Large B-cell Lymphoma Cells.

2α-Hydroxyeudesma-4,11(13)-dien-8β,12-olide (HEDO), a eudesmane-type sesquiterpene lactone belonging to large group of plant terpenoids isolated from Inula britannica, displays cytotoxic activity against diffuse large B cell lymphoma cells in vitro. However, the molecular mechanism of the anticancer effect remains unclear. In this study, we showed that HEDO inhibits cell growth by inducing apoptosis in lymphoma cell lines through its antiproliferative activity. HEDO increases the depolarization of mitochondrial membrane potential and upregulated intracellular reactive oxygen species (ROS). Furthermore, we examined the cell cycle effect, and our results provided evidence that the arrest of the cell cycle at the SubG0/G1 phase plays an important role in the ability of HEDO to inhibit cell growth in Ontario Cancer Institute (OCI)-LY3 lymphoma cells by preventing nuclear factor-kappa B (NF-κB) signaling. In addition, HEDO induced apoptosis by instigating the activation of Bcl-2-associated X (BAX) and cleaved caspase-3, decreasing B-cell lymphoma 2 (BCL2), B-cell lymphoma-extra large (BCL-XL), and procaspase 3 expression levels. Based on these findings, we suggest that HEDO has potential as an anticancer drug of lymphoma by inducing ROS-dependent accumulation of SubG0/G1 arrest and apoptosis in OCI-LY3 cells.

The Revolution in Health Research.

After PhD studies at the University of Toronto, and postdoctoral work in London, Alan worked at the Ontario Cancer Institute and then the Samuel Lunenfeld Research Institute (eventually as Director of Research). As inaugural president of the Canadian Institutes of Health Research (CIHR; 2000-2007), he led the transformation of health research in Canada and an almost tripling of the budget for health research. He then was named executive director of the Global HIV Vaccine Enterprise (2008-2012). Since 2012, Alan has been president of CIFAR, Canada's global research institute, where he has led major initiatives to increase CIFAR's programs of research and global impact, and launched new programs to nurture the world's next generation of researchers. Author of 250 scientific and 50 op-ed and lay publications, Alan has received numerous awards and honors, including induction into the Orders of Canada and Ontario, honorary degrees, the Gairdner Wightman Award, induction into the Canadian Medical Hall of Fame and the Henry Friesen International Prize.

Ernest Armstrong McCulloch. 21 April 1926—20 January 2011

Ernest Armstrong McCulloch was half of the brilliant partnership that discovered haematopoietic stem cells (HSCs) and changed how we think about human tissue generation and regeneration. Based at the Ontario Cancer Institute (now the Princess Margaret Cancer Centre) in Toronto, the haematologist ‘Bun’ McCulloch, together with James E. Till, a physicist with a steel-trap mind, exercised their penchant for adventurous ‘big picture’ thinking in devising experiments to identify stem cells. This exceptional team was the first to demonstrate that HSCs have the dual capacity to self-renew and to differentiate into a vast array of mature haematopoietic cells. Their trainees, as well as investigators elsewhere, built on McCulloch and Till's findings not only to isolate and characterize HSCs and progenitors derived from them, but also to devise therapies for certain blood disorders. Later in his career, Ernest focused on characterizing the malignant cells of human leukaemias and determining the effects of various drugs on leukaemic cell growth. The implications of Till and McCulloch's work continue to be profound and underpin many significant breakthroughs in our knowledge of normal cellular physiology, pathophysiology, tumorigenesis and tissue transplantation. Indeed, regenerative medicine owes its very existence to the stem cell discoveries of McCulloch, Till and others. At times eccentric and demanding, but always well spoken, incisive and erudite, Ernest personified the outstanding research scientist cloaked in Canadian modesty. His legacy lives on in the bright therapeutic future emerging from the rigorous stem cell research being conducted in Canada and around the world.

A Journey in Science: "Not Lost in Translation".

Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by Tak Mak, PhD, Professor, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Princess Margaret Cancer Centre in Toronto. A visionary in the field of cancer, this is the story of Dr. Mak's scientific journey.

BRD4 associates with p53 in DNMT3A‐mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1

The bromodomain and extra terminal (BET) family protein bromodomain containing protein 4 (BRD4) is an epigenetic regulator recently identified as a therapeutic target for several hematological cancers, notably mixed lineage leukemia-fusion acute myeloid leukemia (MLL-AML). Here, we show that the BRD4 bromodomain inhibitor JQ1 is highly active against the p53-wild-type Ontario Cancer Institute (OCI)-AML3 cell line which carries mutations in nucleophosmin (NPM1) and DNA methyltransferase 3 (DNMT3A) genes commonly associated with poor prognostic disease. We find that JQ1 causes caspase 3/7-mediated apoptosis and DNA damage response in these cells. In combination studies, we show that histone deacetylase (HDAC) inhibitors, the HDM2 inhibitor Nutlin-3, and the anthracycline daunorubicin all enhance the apoptotic response of JQ1. These compounds all induce activation of p53 suggesting that JQ1 might sensitize AML cells to p53-mediated cell death. In further experiments, we show that BRD4 associates with acetylated p53 but that this association is not inhibited by JQ1 indicating that the protein–protein interaction does not involve bromodomain binding of acetylated lysines. Instead, we propose that JQ1 acts to prevent BRD4-mediated recruitment of p53 to chromatin targets following its activation in OCI-AML3 cells resulting in cell cycle arrest and apoptosis in a c-MYC-independent manner. Our data suggest that BET bromodomain inhibition might enhance current chemotherapy strategies in AML, notably in poor-risk DNMT3A/NPM1-mutated disease.

Editorial introductions

Editorial introductions

ERRATUM: "SINGLET OXYGEN DETECTION DURING PHOTOSENSITIZATION"

BUHONG LI†¶, HUIYUN LIN, DEFU CHEN, BRIAN C. WILSON and YING GU Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education Fujian Provincial Key Laboratory for Photonics Technology Fujian Normal University, Fujian 350007, P. R. China Department of Laser Medicine Chinese PLA General Hospital, Beijing 100853, P. R. China Department of Medical Biophysics University of Toronto, Ontario Cancer Institute, Toronto Ontario M5G 2M9, Canada ¶bhli@fjnu.edu.cm

IL-12 Immunotherapy: Characterization of a CD4+ Effector Population

Event Abstract Back to Event IL-12 Immunotherapy: Characterization of a CD4+ Effector Population Megan Nelles1, 2*, Caren Furlonger1, Jeffrey A. Medin1, 2, 3 and Christopher J. Paige1, 2, 4 1 University Health Network, Ontario Cancer Institute, Princess Margaret Cancer Centre, Canada 2 University of Toronto, Medical Biophysics, Canada 3 University of Toronto, Institute of Medical Sciences, Canada 4 University of Toronto, Immunology, Canada The ability of interleukin-12 (IL-12) to initiate anti-cancer immune responses is well established, and this cytokine was recently ranked 3rd on a list of agents rated for their potential to treat cancer during the NCI Immunotherapy Agent Workshop. We have therefore used a murine leukaemia model to characterize the immune response initiated by a cell-based immunotherapy approach employing IL-12. This approach leads to protective immunity, but initial rejection is surprisingly dependent primarily on a CD4+ cellular subset. In contrast, injection of recombinant IL-12 leads to CD8+ T cell-mediated rejection. This highlights that the mode of IL-12 delivery has a distinct impact on the immune response initiated. To further characterize this CD4+ effector population, as well as derive mechanistic information, in vitro assays have been established. We have demonstrated that NKT cells play a critical role in activating a DC population that subsequently drives the maturation of these cytotoxic CD4+ T cells, eventually leading to clearance of the leukaemia cells. Though CD4+ T cells are known to possess cytotoxic capacity, little is understood about the physiological role that a CD4+ CTL might play. Description of such a population that arises naturally, without targeted manipulation of the experimental system, is of great interest. Our work begins to address what stimuli are responsible for activation of this CD4+ effector population and the mechanisms they use to mediate cancer eradication. Acknowledgements Research supported by: The Canadian Cancer Society Research Institute; Terry Fox Foundation Program Project, and The Princess Margaret Hospital Foundation. The NIH Tetramer Core Facility provided tetramer reagents. Keywords: cancer immunotherapy, Interleukin-12, CD4-Positive T-Lymphocytes, Cytotoxicity, Lentivirus Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Nelles M, Furlonger C, Medin JA and Paige CJ (2013). IL-12 Immunotherapy: Characterization of a CD4+ Effector Population. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00970 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Megan Nelles, University Health Network, Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada, mnelles@uhnres.utoronto.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Megan Nelles Caren Furlonger Jeffrey A Medin Christopher J Paige Google Megan Nelles Caren Furlonger Jeffrey A Medin Christopher J Paige Google Scholar Megan Nelles Caren Furlonger Jeffrey A Medin Christopher J Paige PubMed Megan Nelles Caren Furlonger Jeffrey A Medin Christopher J Paige Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The lessons of failure

The lessons of failure

Clinical Proteomics

Clinical proteomics involves the analysis of protein expression of disease proteomes, with the aim of solving a specific clinical problem. Discoveries made from proteomicbased studies contribute to the growing need for innovative medical diagnostics for disease detection. Taking into consideration the global health burden of cardiac disease, clinical proteomics is a valuable tool to improve risk stratification associated with this disease. In cardiovascular medicine, the identification of novel proteins, or biomarkers, that are differentially expressed in cardiac disease proteomes may enable early detection of the disease state, thereby preventing progression to disease end points. This review outlines various proteomic platforms and their technical advancements and relates these to the cardiovascular sciences. The entire protein complement of the cell, or proteome, is dynamic and changes in response to the disease state. 1 Proteomic-based experiments can be used to characterize such alterations in protein expression during disease progression. 2 With combined improvements in mass spectrometry (MS) technology as well as innovative molecular biology screening tools, there has been widespread growth in the characterization of cardiac disease proteomes. In fact, proteomic technology has been an important tool in the analysis of heart failure (HF), 3,4 cardiac hypertrophy, 5,6 and dilated cardiomyopathy.7 Several of the overarching aims of such studies include providing greater understanding of general biological mechanisms as well as identifying unique proteins that are clinically useful in the detection of cardiac disease in the early stages or potentially used as novel therapeutic targets. Clinical proteomics continues to benefit from advancements in technologies that allow for fast and consistent identification of proteins with corresponding increases in the dynamic range of proteins detectable in the disease proteome. MS-related technologies have improved in their ability to detect low-abundance proteins as well as membrane proteins and have benefited from sample preprocessing strategies that decrease the complexity of large-scale analyses. With the emergence of different methodologies for biomarker identification, the following 3 criteria must be taken into careful consideration to determine whether the protein is, in fact,

Ambiguous cells: the emergence of the stem cell concept in the nineteenth and twentieth centuries.

This paper elucidates the origins of scientific work on stem cells. From the late nineteenth century onwards, the notion of stem cells became customary in scientific communities of Imperial Germany. Adopting the term Stammzelle from Ernst Haeckel, Theodor Boveri was influential in introducing the concept in embryological studies and early genetics around 1900, describing a capacity of stem cells for self-renewal as well as differentiation. At the same time, blood stem cells were conceptualized by histologists such as Ernst Neumann and Artur Pappenheim in studies of physiological haematopoiesis and various forms of leukaemia. Furthermore, building on Julius Cohnheim's theory that tumours arise from 'embryonic remnants' in the adult body, pathologists aimed at identifying the cells of origin, particularly in the embryo-like teratomas. Embryonic stem cells thus assumed an ambiguous status, partly representing common heritage and normal development, and partly being seen as potential causes of cancer if they had been left behind or displaced during ontogeny. In the 1950s and 1960s experimental research on teratocarcinomas by Leroy Stevens and Barry Pierce in the USA brought together the strands of embryological and pathological work. Alongside the work of Ernest McCulloch and James Till at the Ontario Cancer Institute from the early 1960s on stem cells in haematopoiesis, this led into the beginnings of modern stem cell research.

Cells, Niche, Fate: Meeting Report on the 6th International Meeting of the Stem Cell Network North Rhine Westphalia

In April 2011, leading stem cell researchers from all over the world came together for the 6th International Meeting of the Stem Cell Network North Rhine Westphalia (www .kongress.stammzellen.nrw.de), organized by Hans Scholer (Munster), Oliver Brustle (Bonn), and Peter Horn (Essen). Notably, more than 600 participants, presenting 136 posters, joined the congress in Essen attracted by the scientific program focussing on ‘‘Homing and migration,’’ ‘‘Cell Fate Specification,’’ and ‘‘Disease Modeling.’’ In addition to these wellestablished topics new sessions dealing with ‘‘Nonhuman Primate Pluripotent Stem Cells’’ and ‘‘Niche, Hypoxia, and Metabolism’’ were integrated into the congress program. This report highlights a few of the most interesting presentations from the broad spectrum of stem cell research. The hematopoietic component of marrow consists predominantly of developing erythrocytes and neutrophils: two lineages that start off as proliferating blasts with a high nuclear-to-cytoplasmic ratio, but go on to develop widely different metabolic characteristics and requirements. The idea presented by Michael Cross (Department of Hematology/ Oncology IZKF, University of Leipzig, Germany) is that hematopoiesis may be organized into metabolic regions of the bone marrow, influenced on the one hand by the relative proximity to arterial or sinusoidal vessels, and on the other hand by the metabolism of the intervening cells. It is now generally accepted that stem cells are maintained in areas in which oxygen tension (and with it oxidative damage) is low. In more active multipotent progenitors, however, hypoxia activates glycolysis and results in differentiation. In comparison, high osmolarity maintains the undifferentiated state while reducing glycolysis and increasing the use of glutamine, consistent with a metabolism biased toward nucleic acid synthesis. In this way, the spatial separation of metabolic pathways in distinct compartments may tailor metabolism to function and avoid the accumulation of potentially toxic products (Cross et al., 2008). Working with hematopoietic stem cells (HSC), Norman Iscove (The Ontario Cancer Institute, University Health Network, Toronto, Canada) presented his data on Gata3, a transcription factor and significant regulator of HSC fate. He could identify strong overexpression of Gata3 transcripts and protein in murine marrow cell fractions comprising 30–85% long-term hematopoietic stem cells (LT-HSC) relative to purified intermediate-term (IT-) HSC (Benveniste et al., 2010). Gata3 transcripts were also most highly expressed in fractions of human cord blood cells comprising 5–10% of cells able to stably reconstitute immunodeficient mice. In Gata3-knockin mice expressing eGFP from the endogenous Gata3 promoter, all LT-HSC were located in eGFP+ cells, whereas all IT-HSC were isolated in nonfluorescent fractions, confirming directly the transcriptional activity of the Gata3 locus in LTbut not in IT-HSC. Gata3 protein was cytoplasmic in freshly isolated LT-HSC in the quiescent state, but translocated to the nucleus when he induced the cells to cycle actively in culture. In mice engineered to delete Gata3 conditionally after induction of Cre recombinase, deletion in the steady state had no significant early or late effects on hematopoiesis, as expected, because Gata3 should remain cytoplasmic in quiescent HSC. In marked contrast he could show, when deleted cells from such mice were injected into irradiated recipients they strongly outcompeted control cells expressing Gata3, and this advantage expanded when marrow cells from these primary recipients were used to reconstitute secondary recipients. The HSC autonomy of the regenerative advantage was confirmed in experiments in which Gata3 deletion was induced after injection of conditionally deletable cells together with wild-type cells into wild-type hosts prior to induction of Cre recombinase followed by a test for competitive advantage in secondary hosts. These experiments establish Gata3 acting to constrain the extent of self-renewal/expansion in dividing LT-HSC. The presentation from Denis Corbeil (Biotec, Technische Universitat Dresden, Germany) was focused on the role of prominin-1, a cholesterol-binding protein (alias CD133), that is widely used as a stem and cancer stem cell marker. He and others previously showed that in both stem cell types, prominin-1 is either symmetrically/asymmetrically distributed during cell division (Fonseca et al., 2008; Giebel et al., 2004) or released into the extracellular milieu in association with small membrane vesicles during the process of cellular differentiation. However, molecular mechanisms underlying these phenomena seem to differ according to the origin of the stem/progenitor cells. In neuroepithelial cells, the segregation of the prominin-1-containing apical plasma membrane that is determined by the orientation of the cleavage plane appears to be the essential cause of its symmetrically/

New Translational Possibilities for Microenvironmental Modulation of Radiosensitivity

a Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut; Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California; c Division of Applied Molecular Oncology, Ontario Cancer Institute, Toronto Canada; d Gray Institute for Radiation Oncology and Biology, Oxford University, Oxford, United Kingdom; e Division of Cell Biology, National Cancer Institute, Bethesda, Maryland; and f Radiation Research Program, Division of Cancer Treatment & Diagnosis, National Cancer Institute, Bethesda, Maryland

Sprouty-related Ena/Vasodilator-stimulated Phosphoprotein Homology 1-Domain-containing Protein (SPRED1), a Tyrosine-Protein Phosphatase Non-receptor Type 11 (SHP2) Substrate in the Ras/Extracellular Signal-regulated Kinase (ERK) Pathway

SHP2 is a tyrosine phosphatase involved in the activation of the Ras/ERK signaling pathway downstream of a number of receptor tyrosine kinases. One of the proposed mechanisms involving SHP2 in this context is to dephosphorylate and inactivate inhibitors of the Ras/ERK pathway. Two protein families bearing a unique, common domain, Sprouty and SPRED proteins, are possible candidates because they have been reported to inhibit the Ras/ERK pathway upon FGF activation. We tested whether any of these proteins are likely substrates of SHP2. Our findings indicate that Sprouty2 binds to the C-terminal tail of SHP2, which is an unlikely substrate binding site, whereas SPRED proteins bind to the tyrosine phosphatase domain that is known to be the binding site for its substrates. Overexpressed SHP2 was able to dephosphorylate SPREDs but not Sprouty2. Finally, we found two tyrosine residues on SPRED1 that are required, when phosphorylated, to inhibit Ras/ERK activation and identified Tyr-420 as a specific dephosphorylation target of SHP2. The evidence obtained indicates that SPRED1 is a likely substrate of SHP2, whose tyrosine dephosphorylation is required to attenuate the inhibitory action of SPRED1 in the Ras/ERK pathway.

Roles of CD28, CTLA4, and Inducible Costimulator in Acute Graft-versus-Host Disease in Mice

T cells deficient for CD28 have reduced ability to expand and survive, but still cause graft-versus-host disease (GVHD). Inducible costimulator (ICOS), a member of the CD28 family, is expressed on antigen-activated T cells and plays unique roles in T cell activation and effector function. We hypothesized that ICOS contributes to the development of GVHD in the absence of B7:CD28/CTLA4 costimulation. In this study, we evaluated the roles of CD28, CTLA4, and ICOS in the pathogenesis of acute GVHD after myeloablative allogeneic bone marrow transplantation. Unexpectedly, we found that blocking CD28 and CTLA4 signals using the clinically relevant reagent CTLA4-Ig increases the severity of GVHD mediated by CD4(+) T cells, and that such treatment does not add any benefit to the blockade of ICOS. In contrast, selectively blocking CD28 and ICOS, but not CTLA4, prevents GVHD more effectively than blocking either CD28 or ICOS alone. Taken together, these results indicate that CD28 and ICOS are synergistic in promoting GVHD, whereas the CTLA4 signal is required for T cell tolerance regardless of ICOS signaling. Thus, blocking CD28 and ICOS while sparing CTLA4 represents a promising approach for abrogating pathogenic T cell responses after allogeneic bone marrow transplantation.

Construction and Evaluation of an Anatomically Correct Multi-Image Modality Compatible Phantom for Prostate Cancer Focal Ablation

Focal therapy using lasers is emerging as an alternative strategy for prostate cancer treatment. However, to our knowledge no anatomically correct models are available to test imaging and ablation techniques. Animal models present ethical, anatomical and cost challenges. We designed and validated an inexpensive but anatomically correct prostate phantom incorporating tumor, rectum and urethra that can be used for simulated and experimental magnetic resonance guided focal intervention. Our secondary aim was to asses the phantom using other imaging modalities. The phantom, which was constructed of ballistic gel, includes an 80 gm prostate with urethra, tumor, perineum and rectum. Gadolinium was added to make the gel visible to magnetic resonance imaging. To recreate a tumor an irregularly shaped 5 cc volume of coagulable gel was inserted into the prostate phantom. The phantom was evaluated using magnetic resonance, computerized tomography and transrectal ultrasound. Thermal ablation was delivered via interstitial placement of laser fibers. Magnetic resonance thermometry was done to record real-time tissue temperatures during thermal ablation. With all modalities tested the phantom emulated human prostate anatomy. The coagulable gel tumor allowed us to generate focal thermal lesions. The phantom had magnetic resonance imaging properties comparable to in vivo properties, allowing ablative zones to be accurately assessed and magnetic resonance thermometry to be done. The phantom is a useful tool to test different aspects of thermal focal ablation for prostate cancer using multiple imaging modalities, particularly magnetic resonance. It is inexpensive and easily constructed, and may be considered a valuable model to train on and teach focal therapy.

Activatable Photosensitizers for Imaging and Therapy

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTActivatable Photosensitizers for Imaging and TherapyJonathan F. Lovell†, Tracy W. B. Liu‡, Juan Chen‡, and Gang Zheng*†‡View Author Information Institute of Biomaterials and Biomedical Engineering and Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Ontario M5G 1L7, Canada* To whom correspondence should be addressed. E-mail: [email protected]†Institute of Biomaterials and Biomedical Engineering.‡Department of Medical Biophysics.Cite this: Chem. Rev. 2010, 110, 5, 2839–2857Publication Date (Web):January 27, 2010Publication History Received1 July 2009Published online27 January 2010Published inissue 12 May 2010https://doi.org/10.1021/cr900236hCopyright © 2010 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views17315Altmetric-Citations1335LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (2 MB) Get e-AlertsSUBJECTS:Fluorescence,Oxygen,Peptides and proteins,Photosensitization,Quenching Get e-Alerts

The second cellular therapy of cancer symposium, 27-29 March 2009, Milan, Italy.

The second Cellular Therapy of Cancer Symposium, held in Milan, Italy last March, buoyed by the success of the Inaugural 2006 meeting in Manchester, UK, again brought together leading Wgures in cellular therapy research. The increase in delegate numbers registered in Milan surely reXected the rising interest in the Weld fuelled by recent high proWle publications demonstrating the success of adoptive cell therapy in cancer patients. The meeting was organized by members of the FP6 ATTACK consortium and hosted several scientiWc sessions spanning the research in cellular therapy in commercial and academic environment, the issues of TCR transfer and engineering and of redirected T-cell homing, subset representation and survival, and the latest pre and clinical development. The meeting also hosted a EU-sponsored talk given by Rosanna D’Amario, who summarized opportunities of career development within the FP7 People Programme. The meeting began with invited speakers from the commercial sector describing recent advances in the translation of laboratory studies to the clinical setting. Shahriar Yaghoubi (Stanford University School of Medicine, USA) described how adoptively transferred cells could be monitored in patients using PET imaging. Transferred cells can be imaged following direct labeling or through the use of imaging reporter genes such as the herpes simplex virus type 1 thymidine kinase PET reporter gene, which enable long-term visualization of therapeutic cell location, as well as survival or proliferation. Klaus Kuehlcke (Eufets AG, Germany) discussed GMP production of retroviruses, and methods for the expansion of therapeutic cells for clinical trials and Cliona Rooney (Baylor College of Medicine, USA) detailed how the Wilson Wolf bioreactors could be used to grow vast numbers of cells at densities of 8–11 £ 10 cells/cm. John Campbell (Miltentyi Biotech Ltd.) described how the company have generated “Peptivator” 15 amino acid peptide pools to generate antigen speciWc T-cells and Therese Croughs (Cytheris) presented data from several clinical trials using IL-7 to promote anti-tumor immune responses. The important role that cytokines and lymphodepleting chemotherapy can play in cellular therapy was discussed by several speakers. Charlie Surh (The Scripps Research Institute, USA) described how using cytokine/cytokine antibody complexes can reduce the eVective dose of cytokines required and can induce T-cell activation and non-lymphopenia induced homeostatic proliferation. Pamela Ohashi (Ontario Cancer Institute, Canada) presented data showing how IL-7 can enhance vaccine induced immune responses through multiple mechanisms such as the induction of Th17 cells, antagonization of TGF and inhibition of the negative regulator of T-cell activation, cbl-b. Luca Gattinoni (NCI, Bethesda, USA) and Reno Debets (Erasmus Medical Centre, The Netherlands) described how IL-21 could induce a more naive phenotype in ex vivo expanded T-cells and Luca demonstrated how this could be mimicked with a GSK3 inhibitor inducing T-cells with a naive/stem-cell like phenotype which were more potent in vivo. Michael Jensen (City of Hope National Medical Centre, USA) discussed how IL-15, in combination with selection for CD62L, leads to the generation of central memory T-cells which show enhanced engraftment in animal models. Host lymphodepletion has been shown to induce the proliferation and engraftment of transferred T-cells and Naomi Taylor (Institute de Genetique Moleculaire de Montpellier, J. S. Bridgeman · D. E. Gilham · R. E. Hawkins · E. J. Cheadle (&) Cellular Therapy Group, Department of Medical Oncology, The University of Manchester, Manchester, UK e-mail: echeadle@picr.man.ac.uk